Substituted 3,4-dihydro-pyrimido[1,2a]pyrimidines and 3,4-dihydro-pyrazino[1,2a]pyrimidines, and methods for their preparation and use

ABSTRACT

Substituted 3,4-dihydro-pyrimido[1,2a]pyrimidines and 3,4-dihydro-pyrazino[1,2a]pyrimidines of general formula I, the invention also relates to a method for the production thereof, substance libraries containing these compounds, medicaments which contain these compounds in the production of medicaments for treating pain, urinary incontinence, itching, tinnitus aurium and/or diarrhea and to pharmaceutical compositions containing these compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] The present application is a continuation of International PatentApplication No. PCT/EP01/11702, filed Oct. 10, 2001, designating theUnited States of America and published in German as WO 02/30934 A1, theentire disclosure of which is incorporated herein by reference. Priorityis claimed based on Federal Republic of Germany Patent Application No.100 50 661.5, filed Oct. 13, 2000.

FIELD OF THE INVENTION

[0002] The present application relates to substituted3,4-dihydro-pyrimido[1,2a]pyrimidines and3,4-dihydro-pyrazino[1,2a]pyrimidines, to methods for their production,to substance libraries containing them, to pharmaceutical preparationswhich contain these compounds, to the use of these compounds forproducing pharmaceutical preparations to treat pain, urinaryincontinence, itching, tinnitus aurium and/or diarrhea and topharmaceutical compositions containing these compounds.

BACKGROUND OF THE INVENTION

[0003] The treatment of chronic and non-chronic pain conditions hasgreat importance in medicine. There is a worldwide need for effectivetherapies for patient-friendly and targeted treatment of chronic andnon-chronic pain conditions, especially the successful and satisfactorytreatment of pain for the patient.

[0004] Conventional opioids, such as morphine, are extremely effectivein the treatment of severe to the severest pain. However, their use islimited by known side effects, such as respiratory depression, nausea,sedation, constipation and tolerance development. In addition, they areless effective for neuropathic or incidental pain, from which patientswith tumours suffer in particular.

DESCRIPTION OF THE INVENTION

[0005] The object of the present invention is to provide analgesicicallyeffective compounds which are capable of treating pain, in particularchronic and neuropathic pain. These compounds cause few side effectswhich opioids with μ-receptor affinity, such as morphine, cause. Theside effects include vomiting, nausea, dependency, respiratorydepression or constipation.

[0006] This object is achieved by the compounds of general formula Iwhich are analgesically effective. The compounds according to theinvention are substituted 3,4-dihydro-pyrimido[1,2a]pyrimidines and3,4-dihydro-pyrazino[1,2a]pyrimidines of general formula I

[0007] wherein

[0008] Y represents CR⁸ and

[0009] Z represents N; or

[0010] Y represents N and

[0011] Z represents CR⁹,

[0012] R¹ and R² independently of one another are H; OR¹⁰; SH; SR¹⁰;C₁₋₁₂ alkyl, wherein alkyl is straight-chained or branched and saturatedor unsaturated and unsubstituted or singly or multiply substituted; C₃₋₈cycloalkyl, wherein cycloalkyl is saturated or unsaturated andunsubstituted or singly or multiply substituted; heterocyclyl, whereinheterocyclyl is 3-, 4-, 5-, 6- or 7-membered and is saturated orunsaturated and unsubstituted or singly or multiply substituted; aryl,wherein aryl is unsubstituted or singly or multiply substituted;heteroaryl, wherein heteroaryl is unsubstituted or singly or multiplysubstituted; (C₁₋₆ alkyl)-aryl, wherein C₁₋₆ alkyl is straight-chainedor branched, saturated or unsaturated, and unsubstituted or singly ormultiply substituted, and aryl is unsubstituted or singly or multiplysubstituted; or (C₁₋₆ alkyl)-heteroaryl, wherein C₁₋₆ alkyl isstraight-chained or branched, saturated or unsaturated, andunsubstituted or singly or multiply substituted, and heteroaryl isunsubstituted or singly or multiply substituted,

[0013] wherein if one of R¹ and R² is H, and the other of R¹ and R² isnot H; and if one of R¹ and R² represents aryl, the other of R¹ and R²represents H or C₁₋₁₂ alkyl,

[0014] R³ and R⁴ independently of one another represent H; C₁₋₁₂ alkyl,wherein C₁₋₁₂ alkyl alkyl is straight-chained or branched and saturatedor unsaturated and unsubstituted or singly or multiply substituted; C₃₋₈cycloalkyl, wherein cycloalkyl is saturated or unsaturated andunsubstituted or singly or multiply substituted; aryl, wherein aryl isunsubstituted or singly or multiply substituted; heteroaryl, whereinheteroaryl is unsubstituted or singly or multiply substituted; (C₁₋₆alkyl)-aryl, wherein C₁₋₆ alkyl is straight-chained or branched andsaturated or unsaturated and unsubstituted or singly or multiplysubstituted, and aryl is unsubstituted or singly or multiplysubstituted; or (C₁₋₆ alkyl)-heteroaryl, wherein C₁₋₆ alkyl isstraight-chained or branched and saturated or unsaturated andunsubstituted or singly or multiply substituted, and heteroaryl isunsubstituted or singly or multiply substituted,

[0015] wherein at least one of R³ and R⁴ is H, or

[0016] one of R¹ or R² together with one of R³ or R⁴ forms W, wherein Wrepresents α′-(CH₂)_(n)-β′ where n=3, 4, 5, 6, 7, 8, 9 or 10,α′-CH═CH—CH₂-β′, α′-CH═CH—CH₂—CH₂-β′, α′-CH₂—CH═CH—CH₂-β′,α′-CH₂—CH₂—CH═CH—CH₂—CH₂-β′, α′-O—(CH₂)_(n)-β′ where n=2, 3, 4, 5 or 6,

[0017] where X=CH₂, O or S,

[0018]  and the end of W denoted by α′ is joined to the α-carbon atom ofthe compound of general formula I and the end of W denoted by β′ isjoined to the β-carbon atom of the compound of general formula I,

[0019] the other of R¹ and R² is H or C₁₋₁₂ alkyl, wherein alkyl isstraight-chained or branched and saturated or unsaturated andunsubstituted or singly or multiply substituted, and the other of R³ andR⁴ is H or C₁₋₁₂ alkyl, wherein alkyl is straight-chained or branchedand saturated or unsaturated and unsubstituted or singly or multiplysubstituted,

[0020] R⁵ represents C₁₋₁₂ alkyl, wherein C₁₋₁₂ alkyl isstraight-chained or branched and saturated or unsaturated andunsubstituted or singly or multiply substituted; C₃₋₈ cycloalkyl,wherein cycloalkyl is saturated or unsaturated and unsubstituted orsingly or multiply substituted; heterocyclyl, wherein heterocyclyl is3-, 4-, 5-, 6- or 7-membered and is saturated or unsaturated andunsubstituted or singly or multiply substituted; aryl, wherein aryl isunsubstituted or singly or multiply substituted; heteroaryl, whereinheteroaryl is unsubstituted or singly or multiply substituted; (C₁₋₆alkyl)-aryl, wherein C₁₋₆ alkyl is straight-chained or branched andsaturated or unsaturated and unsubstituted or singly or multiplysubstituted, and aryl is unsubstituted or singly or multiplysubstituted; or (C₁₋₆ alkyl)-heteroaryl, wherein C₁₋₆ alkyl isstraight-chained or branched and saturated or unsaturated andunsubstituted or singly or multiply substituted, and heteroaryl isunsubstituted or singly or multiply substituted, C(═O)R¹¹, CO₂H orCO₂R¹²,

[0021] R⁶, R⁷, R⁸ and R⁹ independently of one another represent H; F;Cl; Br; I; CN; NH₂; NH(C₁₋₆ alkyl); N(C₁₋₆ alkyl)₂; NH((C₁₋₆alkyl)-aryl); N((C₁₋₆ alkyl)-aryl)₂; NH-aryl; N(aryl)₂; NHR¹³; NO₂; OH;SH; O—C₁₋₈ alkyl or S(O)_(p)—C₁₋₈ alkyl, wherein alkyl isstraight-chained or branched and saturated or unsaturated andunsubstituted or singly or multiply substituted and p is 0, 1 or 2;O-aryl or S(O)_(q) aryl, wherein aryl is unsubstituted or singly ormultiply substituted and q is 0, 1 or 2, O—(C₁₋₆ alkyl)-aryl orS(O)_(r)—C₁₋₆ alkyl)-aryl, wherein C₁₋₆ alkyl is straight-chained orbranched and saturated or unsaturated and unsubstituted or singly ormultiply substituted, aryl is unsubstituted or singly or multiplysubstituted, and r is 0, 1 or 2, CO₂H, C(═O)R¹⁴; C₁₋₁₂ alkyl, whereinalkyl is straight-chained or branched and saturated or unsaturated andunsubstituted or singly or multiply substituted; CF₃; C₃₋₈ cycloalkyl,wherein cycloalkyl is saturated or unsaturated and unsubstituted orsingly or multiply substituted; heterocyclyl, wherein heterocyclyl is3-, 4-, 5-, 6- or 7-membered and is saturated or unsaturated andunsubstituted or singly or multiply substituted, aryl, wherein aryl isunsubstituted or singly or multiply substituted; or heteroaryl, whereinheteroaryl is unsubstituted or singly or multiply substituted, or

[0022] R⁶ and R⁷ together form Q, wherein Q representsγ′-CR¹⁵═CR¹⁶—CR¹⁷═CR¹⁸-δ′, the end of Q denoted by γ′ is joined to theγ-carbon atom of the compound of general formula I and the end of Qdenoted by δ′ is connected to the δ-carbon atom of the compound ofgeneral formula I, and Y and Z are as defined above, or

[0023] R⁶ and R⁹ together form T, wherein T representsγ′-CR¹⁹═CR²⁰—CR²¹═CR²²-ε′ or γ′-N═CR²⁰—CR²¹═N-ε′, the end of T denotedby γ′ is joined to the γ-carbon atom of the compound of general formulaI and the end of T denoted by ε′ is joined to the ε-carbon atom of thecompound of general formula I and R⁷ and R⁸ are as defined above,

[0024] R¹⁰ represents C₁₋₈ alkyl, wherein alkyl is straight-chained orbranched and saturated or unsaturated and unsubstituted or singly ormultiply substituted, C₃₋₈ cycloalkyl, wherein cycloalkyl is saturatedor unsaturated and unsubstituted or singly or multiply substituted;heterocyclyl, wherein heterocyclyl is 3-, 4-, 5-, 6- or 7-membered andis saturated or unsaturated and unsubstituted or singly or multiplysubstituted; aryl, wherein aryl is unsubstituted or singly or multiplysubstituted; heteroaryl, wherein heteroaryl is unsubstituted or singlyor multiply substituted; (C₁₋₆ alkyl)-aryl, wherein C₁₋₆ alkyl isstraight-chained or branched and saturated or unsaturated andunsubstituted or singly or multiply substituted and aryl isunsubstituted or singly or multiply substituted; or (C₁₋₆alkyl)-heteroaryl, wherein C₁₋₆ alkyl is straight-chained or branchedand saturated or unsaturated and unsubstituted or singly or multiplysubstituted, and heteroaryl is unsubstituted or singly or multiplysubstituted,

[0025] R¹¹ represents NH₂; NH(C₁₋₆ alkyl); N(C₁₋₆ alkyl)₂; NH((C₁₋₆alkyl)-aryl); N((C₁₋₆ alkyl)-aryl)₂; NH-aryl; N(aryl)₂; C₁₋₈ alkyl,wherein alkyl is straight-chained or branched and saturated orunsaturated and unsubstituted or singly or multiply substituted; C₃₋₈cycloalkyl, wherein cycloalkyl is saturated or unsaturated andunsubstituted or singly or multiply substituted; aryl, wherein aryl isunsubstituted or singly or multiply substituted; heteroaryl, whereinheteroaryl is unsubstituted or singly or multiply substituted; (C₁₋₆alkyl)-aryl, wherein C₁₋₆ alkyl is straight-chained or branched andsaturated or unsaturated and unsubstituted or singly or multiplysubstituted, and aryl is unsubstituted or singly or multiplysubstituted; or (C₁₋₆ alkyl)-heteroaryl, wherein C₁₋₆ alkyl isstraight-chained or branched and saturated or unsaturated andunsubstituted or singly or multiply substituted and heteroaryl isunsubstituted or singly or multiply substituted,

[0026] R¹² represents C₁₋₈ alkyl, wherein alkyl is straight-chained orbranched and saturated or unsaturated and unsubstituted or singly ormultiply substituted; C₃₋₈ cycloalkyl, wherein cycloalkyl is saturatedor unsaturated and unsubstituted or singly or multiply substituted;(C₁₋₆ alkyl)-aryl, wherein C₁₋₆ alkyl is straight-chained or branchedand saturated or unsaturated and unsubstituted or singly or multiplysubstituted, and aryl is unsubstituted or singly or multiplysubstituted,

[0027] R¹³ represents C(═O)CH₃, C(═O) phenyl or C(═O)O-t.-butyl(t-BOC),

[0028] R¹⁴ represents H; NH₂; NH(C₁₋₆ alkyl); N(C₁₋₆ alkyl)₂; NH((C₁₋₆alkyl)-aryl); N((C₁₋₆ alkyl)-aryl)₂; NH-aryl; N(aryl)₂; C₁₋₈ alkyl,wherein alkyl is straight-chained or branched and saturated orunsaturated and unsubstituted or singly or multiply substituted, C₃₋₈cycloalkyl, wherein cycloalkyl is saturated or unsaturated andunsubstituted or singly or multiply substituted, aryl; wherein aryl isunsubstituted or singly or multiply substituted; (C₁₋₆ alkyl)-aryl,wherein C₁₋₆ alkyl is straight-chained or branched and saturated orunsaturated and unsubstituted or singly or multiply substituted, andaryl is unsubstituted or singly or multiply substituted; OC₁₋₈ alkyl,wherein alkyl is straight-chained or branched and saturated orunsaturated and unsubstituted or singly or multiply substituted; OC₃₋₈cycloalkyl wherein cycloalkyl is saturated or unsaturated andunsubstituted or singly or multiply substituted; O-aryl, wherein aryl isunsubstituted or singly or multiply substituted; or O—(C₁₋₆ alkyl)-aryl,wherein C₁₋₆ alkyl is straight-chained or branched and saturated orunsaturated and unsubstituted or singly or multiply substituted, andaryl is unsubstituted or singly or multiply substituted,

[0029] R¹⁵, R¹⁶, R¹⁷ and R¹⁸ independently of one another represent H,F, Cl, Br, I, OH, CN, C₁₋₈ alkyl, wherein alkyl is straight-chained orbranched and saturated or unsaturated and unsubstituted or singly ormultiply substituted, or CO₂H, and

[0030] R¹⁹, R²⁰, R²¹ and R²² independently of one another represent H,F, Cl, Br, I, CN, OH; C₁₋₈ alkyl, wherein alkyl is straight-chained orbranched and saturated or unsaturated and unsubstituted or singly ormultiply substituted, or CO₂H,

[0031] and their pharmaceutically acceptable salts.

[0032] The expressions “C₁₋₆ alkyl,” “C₁₋₈ alkyl” and “C₁₋₁₂ alkyl”include, according to this invention, acyclic saturated or unsaturatedhydrocarbon radicals which can be branched or straight-chained andunsubstituted or singly or multiply substituted, with respectively 1 to6, or 1 to 8, or 1 to 12 carbon atoms, i.e. C₁₋₆ alkanyls, C₂₋₆ alkenylsand C₂₋₆ alkinyls or C₁₋₈ alkanyls, C₂₋₈ alkenyls and C₂₋₈ alkinyls orC₁₋₁₂ alkanyls, C₂₋₁₂ alkenyls and C₁₋₁₂ alkinyls. Alkenyls have atleast one C—C double bond and alkinyls at least one C—C triple bond.Alkyl is advantageously selected from the group comprising methyl,ethyl, n-propyl, 2-propyl, n-butyl, iso-butyl, sec.-butyl, tert.-butyl,n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, 2-hexyl, n-octyl, n-decyl,n-dodecyl; ethylenyl (vinyl), ethinyl, propenyl (—CH₂CH═CH₂, —CH═CH—CH₃,—C(═CH₂)—CH₃), propinyl (—CH—C≡CH), butenyl, butinyl, pentenyl,pentinyl, hexenyl, hexinyl, octenyl and octinyl.

[0033] The expression “C₃₋₈ cycloalkyl” represents, for the purposes ofthis invention, cyclic hydrocarbons with 3 to 8 carbon atoms, which canbe saturated or unsaturated, unsubstituted or singly or multiplysubstituted. C₃₋₈ cycloalkyl is advantageously selected from the groupcomprising cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl undcyclooctenyl. For the purposes of the present invention cyclopropyl,cyclopropyl-2-carboxylic acid, cyclopropyl-2-carboxylic acid ethyl esterand cyclohexyl are particularly preferred.

[0034] The expression “aryl” represents, according to this invention,aromatic hydrocarbons, inter alia phenyls, naphthyls and anthracenyls.The aryl radicals can also be condensed with further saturated,unsaturated or partially unsaturated or aromatic ring systems. Each arylradical may be present in an unsubstituted or singly or multiplysubstituted form, wherein the aryl substituents may be the same ordifferent and in any position of the aryl. Aryl is advantageouslyselected from the group comprising phenyl, 1-naphthyl and 2-naphthyl.For the purposes of this invention particularly preferred aryl radicalsare m-toluyl, p-hydroxy-phenyl, p-methoxyphenyl,4-hydroxy-3-methoxyphenyl, 3,4-dimethoxyphenyl, 2,4-dimethylphenyl,4-fluorophenyl, 1-naphthyl and 2-naphthyl.

[0035] The expression “heteroaryl” represents a 5-, 6- or 7-memberedcyclic aromatic radical which contains at least 1, 2, 3, 4 or 5heteroatoms, wherein the heteroatoms may be the same or different andthe heterocycle can be unsubstituted or singly or multiply substituted;in the case of substitution on the heterocycle the heteroarylsubstituents may be the same or different and in any position of theheteroaryl. The heterocycle can also be part of a bi- or polycyclicsystem. Preferred heteroatoms are nitrogen, oxygen and sulphur. It ispreferred if the heteroaryl radical is selected from the groupcomprising pyrrolyl, indolyl, furyl (furanyl), benzofuranyl, thienyl(thiophenyl), benzothienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl,isoxazoyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl,indolyl, indazolyl, purinyl, pyrimidinyl, indolizinyl, quinolinyl,isoquinolinyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl,wherein the bond with the compounds of general formula I can be made byany arbitrary and possible ring member of the heteroaryl radical. Forthe purposes of this invention particularly preferred heteroarylradicals are pyridin-2-yl, furan-2-yl, 5-methyl-furan-2-yl and5-nitro-furan-2-yl.

[0036] The expressions “(C₁₋₆ alkyl)-aryl” and “(C₁₋₆alkyl)-heteroaryl,” for the purposes of the present invention, mean thatC₁₋₆ alkyl, aryl and heteroaryl have the meanings defined above and arebound by a C₁₋₆ alkyl group to the compound of general formula I.

[0037] The expression “heterocyclyl” represents a 3-, 4-, 5-, 6- or7-membered cyclic organic radical containing at least 1, possibly also2, 3, 4 or 5 heteroatoms, wherein the heteroatoms may be the same ordifferent and the cyclic radical can be saturated or unsaturated, but isnot aromatic, and can be unsubstituted or singly or multiplysubstituted. The heterocycle can also be part of a bi- or polycyclicsystem. Preferred heteroatoms are nitrogen, oxygen and sulphur. It ispreferred if the heterocyclyl radical is selected from the groupcomprising tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl,piperidinyl, piperazinyl and morpholinyl, wherein the bond with thecompound of general formula I (or II, III or IV) can be made by any ringmember of the heterocyclyl radical.

[0038] In conjunction with “alkyl,” “alkanyl,” “alkenyl” and “alkinyl,”the term “substituted” is taken to mean, according to this invention,the substitution of a hydrogen radical by F, Cl, Br, I, CN, NH₂,NH-alkyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl,NH-heterocyclyl, NH-alkyl-OH, N(alkyl)₂, N(alkyl-aryl)₂,N(alkyl-heteroaryl)₂, N(heterocyclyl)₂, N(alkyl-OH)₂, NO, NO₂, SH,S-alkyl, S-aryl, S-heteroaryl, S-alkyl-aryl, S-alkyl-heteroaryl,S-heterocyclyl, S-alkyl-OH, S-alkyl-SH, OH, O-alkyl, O-aryl,O-heteroaryl, O-alkyl-aryl, O-alkyl-heteroaryl, O-heterocyclyl,O-alkyl-OH, CHO, C(═O)C₁₋₆-alkyl, C(═S)C₁₋₆-alkyl, C(═O)aryl, C(═S)aryl,C(═O)C₁₋₆-alkyl-aryl, C(═S)C₁₋₆-alkyl-aryl, C(═O)-heteroaryl,C(═S)-heteroaryl, C(═O)-heterocyclyl, C(═S)-heterocyclyl, CO₂H,CO₂-alkyl, C(═O)NH₂, C(═O)NH-alkyl, C(═O)NH-aryl, C(═O)NH-heterocyclyl,C(═O)N(alkyl)₂, C(═O)N(alkyl-aryl)₂, C(═O)N(alkyl-heteroaryl)₂,C(═O)N(heterocyclyl)₂, SO-alkyl, SO₂-alkyl, SO₂NH₂, SO₃H, cycloalkyl,aryl, heteroaryl or heterocyclyl, wherein multiply substituted radicalsare taken to mean those radicals which are substituted either ondifferent atoms or multiply on the same atoms, for example twice orthree times, for example three times on the same carbon atom as in thecase of CF₃ or —CH₂CF₃, or at various positions as in the case of—CH(OH)—CH═CH—CHCl₂. Multiple substitution can be made with the same orwith different substituents. For the purposes of the present inventionalkyl particularly preferably represents methyl, ethyl, CH₂—CH₂—OH orCF₃.

[0039] With respect to “aryl,” “alkyl-aryl,” “heteroaryl,”“alkyl-heteroaryl,” “heterocyclyl” and “cycloalkyl,” according to thisinvention “singly or multiply substituted” is taken to mean the singleor multiple, for example double, triple or fourfold, substitution of oneor more hydrogen atoms of the ring system by F; Cl, Br, I, CN, NH₂,NH-alkyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl,NH-heterocyclyl, NH-alkyl-OH, N(alkyl)₂, N(alkyl-aryl)₂,N(alkyl-heteroaryl)₂, N(heterocyclyl)₂, N(alkyl-OH)₂, NO, NO₂, SH,S-alkyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-alkyl-aryl,S-alkyl-heteroaryl, S-heterocyclyl, S-alkyl-OH, S-alkyl-SH, OH, O-alkyl,O-cycloalkyl, O-aryl, O-heteroaryl, O-alkyl-aryl, O-alkyl-heteroaryl,O-heterocyclyl, O-alkyl-OH, CHO, C(═O)C₁₋₆-alkyl, C(═S)C₁₋₆-alkyl,C(═O)aryl, C(═S)aryl, C(═O)—C₁₋₆-alkyl-aryl, C(═S)C₁₋₆-alkyl-aryl,C(═O)-heteroaryl, C(═S)-heteroaryl, C(═O)-heterocyclyl,C(═S)-heterocyclyl, CO₂H, CO₂-alkyl, C(═O)NH2, C(═O)NH-alkyl,C(═O)NH-aryl, C(═O)NH-heterocyclyl, C(═O)N(alkyl)₂, C(═O)N(alkyl-aryl)₂,C(═O)N(alkyl-heteroaryl)₂, C(═O)N(heterocyclyl)₂, S(O)-alkyl, S(O)-aryl,SO₂-alkyl, SO₂-aryl, SO₂NH₂, SO₃H, cycloalkyl, aryl, heteroaryl, CF₃,═O, ═S; C₁₋₆-alkanyl, C₂₋₆-alkenyl, C₂₋₆-alkinyl,—C₁₋₆-alkyl-C(O)O—C₁₋₆-alkyl; phenyl, benzyl, naphthyl and/orheterocyclyl; on one or possibly more atoms (wherein one substituentcan, in turn, possibly be substituted). The multiple substitution ismade here with the same or with different substituents. Particularlypreferred substituents for “aryl” are OH, F, CH₃ and O—CH₃. Particularlypreferred substituents for “heteroaryl” are CH₃ and NO₂. Particularlypreferred substituents for “cycloalkyl” are CO₂H and CO₂ ethyl.

[0040] Pharmaceutically acceptable salts according to this invention arethose salts of the compounds according to the invention in accordancewith general formula I which are physiologically acceptable forpharmaceutical use, in particular when applied to humans or othermammals. Pharmaceutically acceptable salts of this type can, forexample, be formed with inorganic or organic acids.

[0041] The pharmaceutically acceptable salts of the compounds accordingto the invention in accordance with general formula I are preferablyformed with hydrochloric acid, hydrobromic acid, sulphuric acid,phosphoric acid, methane sulphonic acid, p-toluene sulphonic acid,carbonic acid, formic acid, acetic acid, oxalic acid, succinic acid,tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid,glutamic acid or aspartic acid. The salts formed are inter aliahydrochlorides, hydrobromides, phosphates, carbonates, hydrogencarbonates, formates, acetates, oxalates, succinates, tartrates,fumarates, citrates and glutaminates. The hydrates of the compoundsaccording to the invention which, for example, can be obtained fromaqueous solution by crystallisation, are also preferred.

[0042] All compounds according to the invention contain at least oneasymmetric center, namely the carbon atom of structure I substituted byR⁵. Therefore, the compounds according to the invention of generalformula I can be present in the form of their racemates, in the form ofthe pure enantiomers and/or diastereomers or in the form of mixtures ofthese enantiomers or diastereomers, and, more precisely, both in theform depicted and as pharmaceutically acceptable salts of thesecompounds. The mixture can be present in any mixing ratio of thestereoisomers. The compounds of general formula I are preferably presentas enantiomer-pure compounds.

[0043] A group of preferred compounds of the present invention is formedby 3,4-dihydro-pyrimido[1,2a]pyrimidines, i.e. compounds of generalformula I, where Y=N and Z=CR⁹, in which one of the radicals R¹ and R²represents OR¹⁰, SR¹⁰, C₁₋₆ alkyl or aryl, one of the radicals R³ and R⁴represents H or C₁₋₆ alkyl, or one of the radicals R¹ and R² togetherwith one of the radicals R³ and R⁴ forms W, wherein W representsα′-CH═CH—CH₂—CH₂-β′,

[0044] or

[0045] and the two other radicals from R¹, R², R³ and R⁴ represents H orC₁₋₁₂ alkyl, R⁵ represents C₃₋₇ cycloalkyl, heteroaryl, C(═O)R¹¹, CO₂Hor CO₂R¹², R⁶ represents H, F, Cl, Br, CN, NO₂, C(═O)R¹⁴, C₁₋₆ alkyl,CF₃ or aryl, R⁷ represents H, F, Cl, Br, CN, NH₂, OH or C₁₋₆ alkyl, R⁹represents H, OH, CF₃ or C₁₋₆ alkyl or R⁶ and R⁹ together form T,wherein T represents γ′-N═CR²⁰—CR²¹N-ε′, R¹⁰ represents C₁₋₈ alkyl oraryl, R¹¹ represents aryl, R¹² represents C₁₋₆ alkyl, R¹⁴ representsOC₁₋₆ alkyl, R²⁰ represents H or CH₂H and R²¹ represents H.

[0046] Particularly preferred compounds of this group are3,4-dihydro-pyrimido[1,2a]pyrimidines of general formula IA

[0047] in which one of the radicals R¹ and R² represents O—(CH₂)₂—OH,S-phenyl, phenyl, 3-methylphenyl, 2,4-dimethylphenyl, 4-hydroxyphenyl,4-methoxyphenyl, 4-hydroxy-3-methoxyphenyl, 3,4-dimethoxyphenyl or2-naphthyl, one of the radicals R³ and R⁴ represents H or methyl, or oneof the radicals R¹ and R² together with one of the radicals R³ and R⁴forms W, wherein W represents α′-CH═CH—CH₂—CH₂-β′,

[0048] and the two other radicals from R¹, R², R³ and R⁴ represent H, R⁵represents cyclopropyl, 2-(C(═O)O-ethyl)-cyclopropyl, cyclohexyl,2-pyridinyl, C(═O) phenyl, CO₂H or CO₂ ethyl, R⁶ represents H, Br, CO₂ethyl or methyl, R⁷ represents H, NH₂, OH or methyl and R⁹ represents H,Cl, OH or CF₃ or R⁶ and R⁹ together form T, wherein T representsγ′-N═C(CO₂H)—CH═N-ε′.

[0049] Preferred dihydro-pyrimido[1,2a]pyrimidines according to theinvention of general formula IA are those which are selected from:

[0050]7-bromo-4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrimido[1,2a]pyrimidine-2-carboxylicacid ethyl ester,

[0051]7-bromo-4-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H-pyrimido[1,2a]pyrimidine-2-carboxylicacid,

[0052]7-bromo-4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrimido[1,2a]pyrimidine-2-carboxylicacid,

[0053]7-bromo-4-(4-hydroxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrimido[1,2-a]pyrimidine-2-carboxylicacid ethyl ester,

[0054]2-bromo-6,6a,7,11b-tetrahydro-4,5,11c-triaza-benzo[c]fluorene-6-carboxylicacid ethyl ester,

[0055]7-bromo-4-(4-methoxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrimido[12a]pyrimidine-2-carboxylicacid,

[0056]7-bromo-4-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H-pyrimido[1,2a]pyrimidine-2-carboxylicacid,

[0057]7-bromo-4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrimido[1,2a]pyrimidine-2-carboxylicacid,

[0058][7-bromo-4-(2-hydroxy-ethoxy)-3,4-dihydro-2H-pyrimido[1,2a]pyrimidin-2-yl]-phenyl-methanone,

[0059][7-bromo-4-(4-hydroxy-3-methoxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrimido[1,2a]pyrimidin-2-yl]-phenyl-methanone,

[0060][7-bromo-4-(4-methoxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrimido[1,2a]pyrimidin-2-yl]-phenyl-methanone,

[0061][7-bromo-4-(4-hydroxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrimido[1,2-a]pyrimidin-2-yl]-phenyl-methanone,

[0062][7-bromo-4-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H-pyrimido[1,2a]pyrimidin-2-yl]-phenyl-methanone,

[0063][7-bromo-4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrimido[1,2a]pyrimidin-2-yl]-phenyl-methanone,

[0064]2-(7-bromo-2-cyclopropyl-3,4-dihydro-2H-pyrimido[1,2a]pyrimidin-4yloxy)-ethanol,

[0065]2-(7-bromo-2-cyclohexyl-3,4-dihydro-2H-pyrimido[1,2a]pyrimidin-4yloxy)-ethanol,

[0066]4-(7-bromo-2-cyclohexyl-3-methyl-3,4-dihydro-2H-pyrimido[1,2a]pyrimidin-4-yl)-phenol,

[0067]7-bromo-4-naphthalen-2-yl-3,4-dihydro-2H-pyrimido[1,2a]pyrimidine-2-carboxylicacid ethyl ester,

[0068] 7-bromo-4-m-tolyl-3,4-dihydro-2H-pyrimido[1,2a]pyrimidine-2carboxylic acid ethyl ester,

[0069]2-[7-bromo-4-(2,4-dimethyl-phenyl)-3,4-dihydro-2H-pyrimido[1,2a]pyrimidin-2-yl]-cyclopropanecarboxylic acid ethyl ester,

[0070]2-[7-bromo-4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrimido[1,2a]pyrimidin-2-yl]-cyclopropanecarboxylic acid ethyl ester,

[0071]7-bromo-4-phenylsulphanyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrimido[1,2-a]pyrimidine,

[0072]2-chloro-6-phenylsulphanyl-8-pyridin-2-yl-7,8-dihydro-6H-pyrimido[1,2-a]pyrimidin-4-yl-amine,

[0073] 6-phenylsulphanyl-8-pyridin-2-yl-7,8-dihydro-6H-pyrimido[1,220a]pyrimidine-2,4-diol,

[0074]6-phenylsulphanyl-8-pyridin-2-yl-2-trifluoromethyl-7,8-dihydro-6H-pyrimido[1,2a]pyrimidine-3-carboxylicacid ethyl ester,

[0075]3-methyl-5,8-methano-9-pyridin-2-yl-5,8,8a,9-tetrahydro-4bH-1,4a,10-triaza-phenanthrene-2,4-diol,

[0076] 5,8-methano-9-pyridin-2-yl-5,8,8a,9-tetrahydro-4bH-1,4a,10-triazaphenanthrene-2,4-diol,

[0077]12-hydroxyl-1,4-methano-5-pyridin-2-yl-1,4a,5,12b-tetrahydro-4H-6,7,8,11,12a-pentaaza-benzo[a]anthracene-10-carboxylicacid, and

[0078] 3-bromo-9-pyridin-2-yl-7,8,8a,9-tetrahydro-4bH-1,4a,10-triaza-phenanthrene,

[0079] and their pharmaceutically acceptable salts.

[0080] A further group of preferred compounds is formed by3,4-dihydro-pyrazino[1,2a]pyrimidines, i.e. compounds of general formulaI, where Y=CR⁸ and Z=N, in which one of the radicals R¹ and R²represents OR¹⁰, SR¹⁰, C₁₋₆ alkyl or aryl, one of the radicals R³ and R⁴represents H or C₁₋₆ alkyl, or one of the radicals R¹ and R² togetherwith one of the radicals R³ and R⁴ form W, wherein W represents

[0081] and the two other radicals from R¹, R², R³ and R⁴ represent H orC₁₋₁₂ alkyl, R⁵ represents C₃₋₇ cycloalkyl, heteroaryl, C(═O)R¹¹, CO₂Hor CO₂R¹², R⁶ represents H, F, Cl, Br, CN, NO₂, C(═O)R¹⁴, C₁₋₆ alkyl,CF₃ or aryl, R⁷ represents H, F, Cl, Br, CN, NH₂, OH or C₁₋₆ alkyl, R⁸represents H, F, Cl, Br, CN, NO₂, O—(C₁₋₆ alkyl)-aryl, CO₂H, CONH₂ orC₁₋₆ alkyl, R¹⁰ represents C₁₋₈ alkyl or aryl, R¹¹ represents aryl, R¹²represents C₁₋₆ alkyl and R¹⁴ represents OC₁₋₆ alkyl. These compoundscan also be present in the form of one of their pharmaceuticallyacceptable salts.

[0082] Particularly preferred compounds of this group are3,4-dihydro-pyrazino[1,2a]pyrimidines of general formula IB

[0083] in which one of the radicals R¹ and R² represent O—(CH₂)₂—OH,S-phenyl, methyl, phenyl, 2,4-dimethylphenyl, 4-hydroxyphenyl,4-methoxyphenyl, 4-hydroxy-3-methoxyphenyl or 3,4-dimethoxyphenyl, oneof the radicals R³ and R⁴ represents H or methyl, or one of the radicalsR¹ and R² together with one of the radicals R³ and R⁴ forms W, wherein Wrepresents

[0084] and the two other radicals from R¹, R², R³ and R⁴ represent H, R⁵represents cyclopropyl, 2-(C(═O)O-ethyl)-cyclopropyl, cyclohexyl,2-pyridinyl, 5-methyl-furan-2-yl, 5-nitro-furan-2-yl, C(═O) phenyl, CO₂Hor CO₂ ethyl, R⁶ represents H, Cl, CN or phenyl, R⁷ represents H, NH₂ orCN and R⁸ represents H, Cl, CN, CO₂H or CONH₂, and theirpharmaceutically acceptable salts.

[0085] Preferred dihydro-pyrazino[1,2a]pyrimidines according to theinvention of general formula IB are those which are selected from:

[0086]4-(4-methoxy-phenyl)-3-methyl-2-(5-nitro-furan-2-yl)-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine,

[0087]2-[4-(4-methoxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrazino[1,2a]pyrimidin-2-yl]-cyclopropanecarboxylic acid ethyl ester,

[0088]4-(4-methoxy-phenyl)-3-methyl-2-(5-methyl-furan-2-yl)-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine,

[0089]4-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine-2-carboxylicacid ethyl ester,

[0090]4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine-2-carboxylicacid ethyl ester,

[0091]4-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine-2-carboxylicacid,

[0092]4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine-2-carboxylicacid,

[0093]4-(4-methoxy-phenyl)-2-(5-nitro-furan-2-yl)-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine,

[0094]2-[4-(2,4-dimethyl-phenyl)-3,4-dihydro-2H-pyrazino[1,2a]pyrimidin-2-yl]-cyclopropanecarboxylic acid ethyl ester,

[0095]2-[4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrazino[1,2a]pyrimidin-2-yl]-cyclopropanecarboxylic acid ethyl ester,

[0096]4-(4-hydroxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine-2-carboxylicacid ethyl ester,

[0097]6,6a,7,11b-tetrahydro-3,5,11c-triaza-benzo[c]fluorene-6-carboxylic acidethyl ester,

[0098]4-phenylsulphanyl-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine-2-carboxylicacid ethyl ester,

[0099]4-phenylsulphanyl-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine-2-carboxylicacid,

[0100]4-(4-methoxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine-2-carboxylicacid,

[0101]4-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine-2-carboxylicacid,

[0102]4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine-2-carboxylicacid,

[0103][4-(2-hydroxy-ethoxy)-3,4-dihydro-2H-pyrazino[1,2a]pyrimidin-2-yl]phenyl-methanone,

[0104][4-(4-hydroxy-3-methoxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrazino[1,2a]pyrimidin-2-yl]-phenyl-methanone,

[0105][4-(4-methoxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrazino[1,2a]pyrimidin-2-yl]-phenyl-methanone,

[0106][4-(4-hydroxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrazino[1,2a]pyrimidin-2-yl]-phenyl-methanone,

[0107]2-cyclopropyl-4-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H-pyrazino[1,2-a]pyrimidine,

[0108]2-cyclopropyl-4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine,

[0109]2-(2-cyclohexyl-3,4-dihydro-2H-pyrazino[1,2a]pyrimidin-4-yloxy)ethanol,

[0110]2-cyclohexyl-4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine,

[0111]4-methyl-2-(5-nitro-furan-2-yl)-4-phenyl-3,4-dihydro-2H-pyrazino[1,2-a]pyrimidine,

[0112]2-(4-methyl-4-phenyl-3,4-dihydro-2H-pyrazino[1,2a]pyrimidin-2-yl)-cyclopropanecarboxylic acid ethyl ester,

[0113] 4-phenyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine,

[0114]4-phenyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine-9-carboxylicacid,

[0115]6-amino-7-chloro-4-phenyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrazino[1,2-a]pyrimidine-9-carboxylicacid amide,

[0116]2-phenylsulphanyl-3-pyridin-2-yl-2,3-dihydro-1H-pyrimido[1,2a]quinolin-10-ol,

[0117]4-phenylsulphanyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine-9-carboxylicacid,

[0118]6-amino-7-chloro-4-phenylsulphanyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine-9-carboxylicacid amide,

[0119]7-phenyl-4-phenylsulphanyl-2-pyridin-2-yl-3,4-.dihydro-2H-pyrazino[1,2a]pyrimidine-9-carbonitrile,and

[0120]5,8-methano-9-pyridin-2-yl-5,8,8a,9-tetrahydro-4bH-2,4a,10-triazaphenanthrene,

[0121] 1-chloro-5,8-methano-9-pyridin-2-yl-5,8,8a,9-tetrahydro-4bH-2,4a,10-triaza-phenanthrene-3,4-dicarbonitrile,

[0122] and their pharmaceutically acceptable salts.

[0123] The invention also relates to a method for producing thecompounds of structure I and their pharmaceutically acceptable salts.

[0124] wherein Y, Z and R¹ to R⁷ are as defined above.

[0125] The method of the invention comprises

[0126] a heteroarylamine of general formula II

[0127] wherein Y, Z, R⁶ and R⁷ are as defined above, with the provisothat if R⁶ and R⁷ form Q as defined above, the end of Q denoted by γ′ isjoined to the γ-carbon atom of the heteroarylamine of general formula IIand the end of Q denoted by δ′ is joined to the δ-carbon atom of theheteroarylamine of general formula II, and that if R⁶ and R⁹ form T asdefined above, the end denoted by γ′ is joined to the γ-carbon atom ofthe heteroarylamine of general formula II and the end denoted by ε′ isjoined to the ε-carbon atom of the heteroarylamine of general formulaII,

[0128] is reacted with an aldehyde of general formula III

[0129] wherein R⁵ is as defined above,

[0130] and with an olefin of general formula IV

[0131] wherein R¹, R², R³ and R⁴ are as defined above, with the provisothat if one of the radicals R¹ and R² together with one of the radicalsR³ and R⁴ forms W, the end of W denoted by α′ is joined to the α-carbonatom of the olefin of general formula IV and the end of W denoted by β′is joined to the β-carbon atom of the olefin of general formula IV,

[0132] in the presence of an acid.

[0133] Heteroarylamines of general formula IIA

[0134] wherein R⁶, R⁷ and R⁹ are as defined above for formula II, areused to produce the 3,4-dihydro-pyrimido[1,2a]pyrimidines according tothe invention of general formula IA in the method according to theinvention.

[0135] To produce the 3,4-dihydro-pyrazino[1,2a]pyrimidines according tothe invention of general formula IB, heteroarylamines of general formulaIIB

[0136] wherein R⁶ to R⁸ are as defined above for formula II, are used inthe method according to the invention.

[0137] The method according to the invention is preferably carried outin a “one pot” reaction in which a respective heteroarylamine of generalformula II, a respective aldehyde of general formula III and arespective olefin of general formula IV are simultaneously reacted withone another.

[0138] The method according to the invention can also be carried out insemi- or fully-automated form as a parallel synthesis of a group ofcompounds according to the invention of general formula I.

[0139] The acid used is an inorganic or organic proton acid or Lewisacid. The reaction is preferably carried out in the presence of anorganic acid, for example acetic acid, methane sulphonic acid or, inparticular, trifluoroacetic acid.

[0140] The production method according to the invention can be carriedout in any suitable solvent in which the reactants sufficientlydissolve. Organic solvents, for example dichloromethane or, inparticular, acetonitrile are preferred as solvents.

[0141] The compounds according to the invention of general formula I areexpediently produced according to the invention at a temperature of 0 to100° C., in particular at 15 to 40° C. The reaction time is preferably15 minutes to 12 hours and can be adapted to the respectiverequirements.

[0142] The heteroarylamines of general formula II, the aldehydes ofgeneral formula III and the olefins of general formula IV used in themethod according to the invention are commercially available (fromAcros, Geel; Avocado, Port of Heysham; Aldrich, Deisenhofen; Fluka,Seelze; Lancaster; Mülheim; Maybridge, Tintagel; Merck, Darmstadt;Sigma, Deisenhofen; TCI, Japan) or can be produced by methods generallyknown in the prior art.

[0143] The compounds according to the invention of general formula I canbe isolated both as a free base and as a salt. The free base of thecompound of general formula I is conventionally obtained after thereaction by the method according to the invention described above andsubsequent conventional working up. The base obtained in this way canthen be converted into the corresponding salt, for example by reactionwith an inorganic or organic acid, preferably with hydrochloric acid,hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonicacid, p-toluene sulphonic acid, carbonic acid, formic acid, acetic acid,oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid,lactic acid, citric acid, glutamic acid or aspartic acid. The saltsformed are inter alia hydrochlorides, hydrobromides, phosphates,carbonates, hydrogen carbonates, formates, acetates, oxalates,succinates, tartrates, fumarates, citrates and glutaminates. Theparticularly preferred hydrochloride formation can also be brought aboutby reacting the base dissolved in a suitable organic solvent withtrimethylsilyl chloride (TMSCI).

[0144] If the compounds of general formula I are obtained as racematesor as mixtures of their various enantiomers and/or diasteriomers in theproduction method according to the invention, these mixtures can beseparated by methods well known in the art. Suitable methods are interalia chromatographic methods of separation, in particular liquidchromatography methods under normal and elevated pressure, preferablyMPLC and HPLC methods, and methods of fractional crystallisation. Inparticular individual enantiomers can be separated from one another, forexample by means of HPLC on the chiral phase or by crystallisation ofdiastereomeric salts formed with chiral acids, for instance (+)-tartaricacid, (−)-tartaric acid or (+)-10-camphoric sulphonic acid.

[0145] The present invention also relates to a substance librarycontaining at least one compound of general formula I as defined above.The substance library according to the invention preferably contains atleast 15 and, in particular at least 30, compounds of general formula I.

[0146] For the purposes of the present invention a “substance library”is taken to mean a group of compounds which are produced by the samemethod under the same or virtually the same reaction conditions and withvariation of a reagent or a plurality of reagents. A substance libraryof this type can contain the library members both as individual purecompounds and as a mixture of these compounds. Medical screening by oneor more in vitro screening methods, for example, may be carried out inautomated form with the aid of this substance library.

[0147] The compounds according to the invention have proven to beanalgesically effective. Therefore, the present invention also relatesto a pharmaceutical preparation containing at least one of the compoundsaccording to the invention and as defined above, of general formula I orone of their pharmaceutically acceptable salts. The compounds accordingto the invention can be present in the pharmaceutical preparationaccording to the invention as a pure isomer, in particular a pureenantiomer or a pure diastereomer but also as a racemic or non-racemicmixture. It is preferred that the pharmaceutical preparation contains apharmaceutically acceptable salt of the compounds according to theinvention, in particular a hydrochloride.

[0148] The invention also relates to the use of at least one compoundaccording to the invention of general formula I, including itsdiasteriomers or enantiomers, also as racemates or an enantiomer mixturein the form of its free base or a salt formed with a physiologicallyacceptable acid, in particular the hydrochloride salt, to produce apharmaceutical preparation for treating pain.

[0149] It has surprisingly been found that the compounds according tothe invention of general formula I are very suitable for furtherindications, in particular for treating urinary incontinence, itching,tinnitus aurium and/or diarrhea. The invention therefore also relates tothe use of at least one compound according to the invention of generalformula I, including a pharmaceutically acceptable salt, to produce apharmaceutical preparation for treating urinary incontinence, itching,tinnitus aurium and/or diarrhea.

[0150] Furthermore, the present invention also relates to pharmaceuticalcompositions containing at least one compound of general formula I asdefined above or one of its pharmaceutically acceptable salts and one ormore pharmaceutical auxiliaries.

[0151] The pharmaceutical preparations and compositions according to theinvention can be present in liquid, semi-solid or solid dosage forms andin the form of, for example injection solutions, drops, liquids, syrups,sprays, suspensions, granules, tablets, pellets, transdermal therapeuticsystems, capsules, plasters, suppositories, ointments, creams, lotions,gels, emulsions or aerosols and, in addition to at least one compoundaccording to the invention of general formula I, contain pharmaceuticalauxiliaries such as excipients, fillers, solvents, diluents,surface-active substances, dyes, preservatives, exploding agents,lubricants, flavourings and/or binders depending on the galenic form.These auxiliaries can, for example, be: water, ethanol, 2-propanol,glycerol, ethylene glycol, propylene glycol, polyethylene glycol,polypropylene glycol, glucose, fructose, lactose, saccharose, dextrose,molasses, starch, modified starch, gelatines, sorbitol, inositol,mannitol, microcrystalline cellulose, methyl cellulose, carboxylmethylcellulose, cellulose acetate, shellac, cetyl alcohol,polyvinylpyrrolidone, paraffins, waxes, natural and synthetic rubbers,acacia gum, alginates, dextran, saturated and unsaturated fatty acids,stearic acid, magnesium stearate, zinc stearate, glyceryl stearate,sodium lauryl sulphate, edible oils, sesame oil, coconut oil, peanutoil, soya bean oil, lecithin, sodium lactate, polyoxyethylene andpolyoxypropylene fatty acid ester, sorbitan fatty acid ester, sorbicacid, benzoic acid, citric acid, ascorbic acid, tannic acid, sodiumchloride, potassium chloride, magnesium chloride, calcium chloride,magnesium oxide, zinc oxide, silicon dioxide, titanium oxide, titaniumdioxide, magnesium sulphate, zinc sulphate, calcium sulphate, potash,calcium phosphate, dicalcium phosphate, potassium bromide, potassiumiodide, talc, kaolin, pectin, crospovidon, agar and bentonite.

[0152] The choice of auxiliaries and the amount thereof to be useddepends on whether the pharmaceutical preparation is to be appliedorally, subcutaneously, parenterally, intravenously, vaginally,pulmonally, intraperitoneally, transdermally, intramuscularly, nasally,buccally, rectally or topically, for example to infections of the skin,the mucous membranes or the eyes. Preparations in the form of tablets,dragees, capsules, granules, drops, liquids and syrups inter alia aresuitable for oral application, solutions, suspensions, easilyreconstitutable powders for inhalation and sprays inter alia aresuitable for parenteral, topical and inhalative application. Compoundsaccording to the invention of general formula I in a deposit indissolved form or in a plaster, optionally with the addition ofsubstances promoting skin penetration, are suitable percutaneousapplication preparations. Rectally, transmucosally, parenterally, orallyor percutaneously applicable preparation forms can release the compoundsaccording to the invention of general formula I with a delay.

[0153] The pharmaceutical preparations and compositions according to theinvention are produced with the aid of agents, devices, methods andprocesses well known in the art of pharmaceutical formulation, asdescribed, for example, in “Remington's Pharmaceutical Sciences,” EditorA. R. Gennaro, 17th Edition, Mack Publishing Company, Easton, Pa. (1985)in particular in Part 8, Chapters 76 to 93.

[0154] Therefore, for example, a solid formulation, such as a tablet,the active ingredient of the pharmaceutical preparation, i.e. a compoundof general formula I or one of its pharmaceutically acceptable salts,can be granulated with a pharmaceutical excipient, for exampleconventional tablet ingredients, such as corn starch, lactose,saccharose, sorbitol, talc, magnesium stearate, dicalcium phosphate orpharmaceutically acceptable rubbers, and pharmaceutical diluents, suchas water, in order to form a solid composition containing a compoundaccording to the invention or a pharmaceutically acceptable salt thereofin a homogeneous distribution. A homogeneous distribution here is takento mean that the active ingredient is uniformly distributed over theentire composition so it can be readily subdivided into uniformly actingsingle dose forms, such as tablets, pills or capsules. The solidcomposition is then subdivided into single dose forms. The tablets orpills of the pharmaceutical preparation according to the invention or ofthe compositions according to the invention can also be coated orcompounded in another way in order to provide a dose form with delayedrelease. Suitable coating means are inter alia polymeric acids andmixtures of polymeric acids with materials such as shellac, cetylalcohol and/or cellulose acetate.

[0155] The amount of active ingredient to be administered to the patientvaries and is dependent on the weight, age and history of illness of thepatient and on the method of application, the indication and theseverity of the disease. Conventionally 0.1 to 5,000 mg/kg, inparticular 1 to 500 mg/kg, preferably 2 to 250 mg/kg of bodyweight of atleast one compound according to the invention of general formula I areapplied.

[0156] The following examples serve to describe the present invention inmore detail.

EXAMPLES

[0157] The chemicals and solvents used were commercially obtained fromone of the following suppliers: Acros, Geel; Avocado, Port of Heysham;Aldrich, Deisenhofen; Fluka, Seelze; Lancaster, Mülheim; Maybridge,Tintagel; Merck, Darmstadt; Sigma, Deisenhofen; TCI, Japan; or producedby methods known generally in the prior art.

[0158] Chromatographic purification took place on a HPLC-RP-18 columnfrom Macherey-Nagel; material NUCLEOSIL 100-3 C₁₈-HD approximately 100mm (VarioPrep), internal diameter 21 mm; eluent water/methanol,gradient: 50-100 % in about 18 min, flow: 10 ml/min; detection: UV,Beckman 168 PDA.

[0159] General Instruction AAV (Semi-automated Synthesis)

[0160] A small round-bottomed tube made of glass (diameter 16 mm, length125 mm) with a thread was provided with an agitator and closed by ascrew lid with septum. The tube was placed in the agitator blockadjusted to 20° C. The following reagents were then added in successionusing a pipette:

[0161] 1 ml of a solution of trifluoroacetic acid, 0.1 M, andheteroarylamine components II, 0.1 M, in acetonitrile;

[0162] 1 ml of a 0.11 M solution of the aldehyde III in acetonitrile;

[0163] 1 ml of a 0.3 M solution of the olefin IV in acetonitrile.

[0164] The reaction mixture was stirred for 10 hours at 20° C. in one ofthe agitator blocks. The reaction solution was then filtered off. Thetube was rinsed twice with 1.5 ml of a 7.5% NaHCO₃ solutionrespectively.

[0165] The rack with the samples was placed manually onto the working upunit. 2 ml ethylacetate were added to the reaction mixture on a vortexerand shaken. The mixture was briefly centrifuged in the centrifuge toform the phase boundary. The phase boundary was detected visually andthe organic phase pipetted off. In the next step 2 ml ethylacetate wereadded to the aqueous phase again, the mixture shaken, centrifuged andthe organic phase pipetted off. The combined organic phases were driedover 2.4 g MgSO₂ (granulated). The solvent was removed in a vacuumcentrifuge.

[0166] Each sample was characterized using ESI-MS and/or NMR. Massspectrometric investigations (ESI-MS) were carried out using a massspectrometer from Finnegan, LCQ Classic. ¹H-NMR investigations of thecompounds according to the invention were carried out using a 300 MHzDPX Advance NMR apparatus from Bruker.

[0167] Examples 1 to 61 (see Table 1) were produced in accordance withthe cited AAV. Examples 43 to 45 were purified by means ofreversed-phase HPLC. TABLE 1 Calculated Ascertained Example mass massName 1 366.37 367.34-(4-methoxy-phenyl)-3-methyl-2-(5-nitro--furan-2-yl)-3,4-dihydro-2H-pyrazino[1,2a]-pyrimidine 2 367.44 368.42-[4-(4-methoxy-phenyl)-3-methyl-3,4-dihydro--2H-pyrazino[1,2a]pyrimidin-2-yl]-- cyclopropane carboxylic acid ethyl ester3 335.4 336.24-(4-methoxy-phenyl)-3-methyl-2-(5-methyl--furan-2-yl)-3,4-dihydro-2H-pyrazino[1,2a]-pyrimidine 4 343.38 344.24-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H--pyrazino[1,2a]pyrimidine-2--carboxylic acid ethyl ester 5 313.35 314.14-(4-methoxy-phenyl)-3,4-dihydro-2H--pyrazino[1,2a]pyrimidine-2-carboxylic acid ethyl ester 6 392.25 391.1/7-bromo-4-(4-methoxy-phenyl)-3,4-dihydro-2H-- 393.1pyrimido[1,2a]pyrimidine-2-- carboxylic acid ethyl ester 7 315.32 316.24-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H--pyrimido[1,2a]pyrimidine-2-carboxylic acid 8 394.22 393.2/7-bromo-4-(3,4-dimethoxy-phenyl)-3,4-dihydro--2H- 395.1pyrimido[1,2a]pyrimidine-2-carboxylic acid 9 285.3 286.24-(4-methoxy-phenyl)-3,4-dihydro-2H--pyrazino[1,2a]pyrimidine-2-carboxylic acid 10 364.2 363.2/7-bromo-4-(4-methoxy-phenyl)-3,4-dihydro-2H-- 365.0pyrimido[1,2a]pyrimidine-2-carboxylic acid 11 352.34 353.44-(4-methoxy-phenyl)-2-(5-nitro-furan-2-yl)-3,4-- dihydro2H-pyrazino[1,2a]pyrimdine 12 351.44 352.42-[4-(2,4-dimethyl-phenyl)-3,4-dihydro-2H--pyrazino[1,2a]pyrimidin-2-yl]-- cyclopropane carboxylic acid ethyl ester13 353.42 354.3 2-[4-(4-methoxy-phenyl)-3,4-dihydro-2H--pyrazino[1,2a]pyrimidin-2-yl]-- cyclopropane carboxylic acid ethyl ester14 313.35 314.3 4-(4-hydroxy-phenyl)-3-methyl-3,4-dihydro-2H--pyrazino[1,2a]pyrimidine-2--carboxylic acid ethyl ester 15 392.25 391.4/7-bromo-4-(4-hydroxy-phenyl)-3-methyl-3,4-- dihydro-2H- 393.0pyrimido[1,2a]pyrimidine-2--carboxylic acid ethyl ester 16 295.34 296.36,6a,7,11b-tetrahydro-3,5,11c-triaza-- benzo[c]fluorene-6- carboxylicacid ethyl ester 17 374.24 373.3/2-bromo-6,6a,7,11b-tetrahydro-4,5,11c-triaza-- 375.3benzo[c]fluoren-6-carboxylic acid ethyl ester 18 315.39 316.34-phenylsulphanyl-3,4-dihydro-2H-pyrazino[1,2a]-pyriniidine-2-carboxylic acid ethyl ester 19 287.34 288.24-phenylsulphanyl-3,4-dihydro-2H-pyrazino[1,2a]- pyrimidine-2-carboxylicacid 20 299.32 300.2 4-(4-methoxy-phenyl)-3-methyl-3,4-dihydro--2H-pyrazino[1,2a]pyrimidine-2-carboxylic acid 21 378.23 377.1/7-bromo-4-(4-methoxy-phenyl)-3-methyl-3,4--dihydro-2H- 379.1pyrimido[12a]pyrimidine-2-carboxylic acid 22 315.32 316.24-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H--pyrazino[1,2a]pyrimidine-2-carboxylic acid 23 394.22 393.1/7-bromo-4-(3,4-dimethoxy-phenyl)-3,4-dihydro--2H- 395.1pyrimido[1,2a]pyrimidine-2-carboxylic acid 24 285.3 286.24-(4-methoxy-phenyl)-3,4-dihydro-2H--pyrazino[1,2a]pyrimidine-2-carboxylic acid 25 364.2 363.1/7-bromo-4-(4-methoxy-phenyl)-3,4-dihydro-2H-- 365.1pyrimido[1,2a]pyrimidine-2-carboxylic acid 26 299.32 300.2[4-(2-hydroxy-ethoxy)-3,4-dihydro-2H--pyrazino[1,2a]pyrimidin-2-yl]-phenyl-methanone 27 378.23 379.1[7-bromo-4-(2-hydroxy-ethoxy)-3,4-dihydro-2H--pyrimido[1,2a]pyrirnidin-2-yl]-phenyl-methanone 28 375.42 374.2/[4-(4-hydroxy-3-methoxy-phenyl)-3-methyl-3,4-- dihydro- 376.22H-pyrazino[1,2a]pyrimidin-2-yl]--phenyl-methanone 29 454.32 451.2/[7-bromo-4-(4-hydroxy-3-methoxy-phenyl)-3-methyl-3,4- 453.1dihydro-2H-pyrimido[1,2a]-pyrimidin-2-yl]-phenyl- methanone 30 359.42360.2 [4-(4-methoxy-phenyl)-3-methyl-3,4-dihydro--2H-pyrazino[1,2a]pyrimidin-2-yl]-phenyl-methanone 31 438.32 437.1/[7-bromo-4-(4-methoxy-phenyl)-3-methyl-3,4-- dihydro-2H- 439.1pyrimido[1,2a]pyrimidin-2-yl]--phenyl-metbanone 32 345.4 345.2[4-(4-hydroxy-phenyl)-3-methyl-3,4-dihydro--2H-pyrazino[1,2a]pyrimidin-2-yl]-phenyl--methanone 33 424.3 423.1/[7-bromo-4-(4-hydroxy-phenyl)-3-methyl-3,4--dihydro-2H- 425.1pyrimido[1,2a]pyrimidin-2-yl]--phenyl-methanone 34 454.32 453.2/[7-bromo-4-(3,4-dimethoxy-phenyl)-3,4-dihydro--2H- 455.1pyrimido[1,2a]pyrimidin-2-yl]-phenyl--methanone 35 424.3 423.2/[7-bromo-4-(4-methoxy-phenyl)-3,4-dihydro-2H- 425.1pyrimido[1,2a]pyrimidin-2-yl]-phenyl-methanone 36 314.18 313.1/2-(7-bromo-2-cyclopropyl-3,4-dihydro-2H-- 315.1pyrimido[1,2a]pyrimidin-4-yloxy)-ethanol 37 311.38 312.22-cyclopropyl-4-(3,4-dimethoxy-phenyl)-3,4-- dihydro-2H-pyrazino[1,2a]pyrimidine 38 281.35 282.22-cyclopropyl-4-(4-methoxy-phenyl)-3,4-- dihydro-2H-pyrazino[1,2a]pyrimidine 39 277.36 278.22-(2-cyclohexyl-3,4-dihydro-2H-pyrazmo[1,2a]-pyrimidm-4- yloxy)-ethanol40 356.26 357.2 2-(7-bromo-2-cyclohexyl-3,4-dihydro-2H--pyrimido[1,2a]pyrimidin-4-yloxy)-ethanol 41 402.34 403.14-(7-bromo-2-cyclohexyl-3-methyl-3,4-dihydro-2H-pyrimido[1,2a]pyrimidin-4-yl)-phenol 42 323.43 324.22-cyclohexyl-4-(4-methoxy-phenyl)-3,4--dihydro-2H-pyrazino[1,2a]pyrimidine 43 412.29 413.17-bromo-4-naphthalin-2-yl-3,4-dihydro-2H--pyrimido[1,2a]pyrimidine-2--carboxylic acid ethyl ester 44 376.25 375.4/7-bromo-4-m-tolyl-3,4-dihydro-2H-pyrimido-[1,2- 377.4a]pyrimidme-2-carboxylic acid ethyl ester 45 430.35 431.12-[7-bromo-4-(2,4-dimethyl-phenyl)-3,4-dihydro--2H-pyrimido[1,2a]pyrimidin-2-yl]--cyclopropane carboxylic acid ethyl ester46 432.32 431.4/ 2-[7-bromo-4-(4-methoxy-phenyl)-3,4-dihydro--2H- 433.4pyrimido[1,2a]pyrimidin-2-yl]--cyclopropane carboxylic acid ethyl ester47 336.35 337.34-methyl-2-(5-nitro-furan-2-yl)-4-phenyl-3,4--dihydro-2H-pyrazino[1,2a]pyrimidine 48 339.44 338.32-(4-methyl-4-phenyl-3,4-dihydro-2H--pyrazino[1,2a]pyrimidin-2-yl)--cyclopropane carboxylic acid ethyl ester49 320.41 321.2 4-phenylsulphanyl-2-pyridin-2-yl-3,4-dihydro-2H--pyrazino[1,2a]pyrimidine 50 364.42 365.24-phenylsulphanyl-2-pyridin-2-yl-3,4-dihydro-2H--pyrazino[1,2a]pyrimidine-9-carboxylic acid 51 412.9 413.36-Amino-7-chlor-4-phenylsulphanyl-2-pyridin-2--yl-3,4-dihydro-2H-pyrazino[1,2a]pyrimidin-9--carboxylic acid amide 52 421.52422.4 7-phenyl-4-phenylsulphanyl-2-pyridin-2-yl-3,4--dihydro-2H-pyrazino[1,2a]pyrimidine-9--carbonitrile 53 343.23 343.27-bromo-4-phenylsulphanyl-2-pyridin-2-yl-3,4--dihydro-2H-pyrimido[1,2a]pyrimidine 54 369.87 370.32-chloro-6-phenylsulphanyl-8-pyridin-2-yl-7,8--dihydro-6H-pyrimido[1,2a]pyrimidin-4-yl-amine 55 352.41 353.36-phenylsulphanyl-8-pyridin-2-yl-7,8-dihydro-6H--pyrimido[1,2a]pyrimidin-2,4-diol 56 460.48 461.36-phenylsulphanyl-8-pyridin-2-yl-2-trifluormethyl--7,8-dihydro-6H-pyrimido[1,2a]pyrimidine-3--carboxylic acid ethyl ester 57276.35 277.45,8-methano-9-pyridin-2-yl-5,8,84,9-tetrahydro--4bH-2,44,10-triaza-phenanthrene 58 360.82 324.31-chloro-5,8-methano-9-pyridin-2-yl-5,8,8a,9--tetrahydro- (M—CI)4bH-2,44,10-triaza-phenanthren-e-3,4-dicarbonitrile 59 388.4 324.112-hydroxy-1,4-methano-5-pyridin-2-yl--1,4a,5,12b- (M—COOH—OH)etrahydro-4H-6,7,8,11,12a--pentaaza-benzo[a]anthracene-10- carboxylicacid 60 322.36 323.23-methyl-5,8-methano-9-pyridin-2-yl-5,8,8a,9--tetrahydro-4bH-1,44,10-triaza-phenanthren-e-2,4-diol 61 308.35 309.35,8-methano-9-pyridin-2-yl-5,8,84,9-tetrahydro--4bH-1,4a,10-triaza-phenanthrene-2,4-diol 62 343.23 343.23-bromo-9-pyridin-2-yl-7,8,84,9-tetrahydro--4bH-1,44,10-triaza-phenanthrene

[0168] Pharmacological Tests

[0169] Compounds according to the invention were investigated withrespect to their pharmacological properties using methods described byJ. P. Devlin in “High throughput screening—the discovery of bioactivesubstances,” Marcel Dekker, New York, 1997, pages 275 to 453. Theresults of these tests are summarized in Tables 2 and 3, and demonstratethe analgesic efficacy of the compounds according to the invention.TABLE 2 K_(i) Value of the μ-opiate Receptor Bond Example K_(i) (μM) 511.4 52 1.4 53 2.5

[0170] TABLE 3 % inhibition of NMDA/MK801-binding site Example %inhibition (10 pM) 51 40 52 47 53 44 61 40 62 40

[0171] Pharmaceutical Formulation of a Pharmaceutical PreparationAccording to the Invention

[0172] 1 g of the hydrochloride of4-(3,4-dimethoxy-phenyl)3,4-dihydro-2H-pyrazino[1,2a]pyrimide-2-carboxylic acid was dissolved in 11 water at ambienttemperature for injection purposes and subsequently adjusted to isotonicconditions by adding sodium chloride.

What is claimed is:
 1. A compound of formula I

wherein Y represents CR⁸ and Z represents N; or Y represents N and Zrepresents CR⁸, R¹ and R² independently of one another represent H;OR¹⁰; SH; SR¹⁰; C₁₋₁₂ alkyl, which is straight-chain or branched andsaturated or unsaturated and unsubstituted or singly or multiplysubstituted; C₃₋₈ cycloalkyl, wherein the cycloalkyl is saturated orunsaturated and unsubstituted or singly or multiply substituted;heterocyclyl, wherein the heterocyclyl is 3-, 4-, 5-, 6- or 7-memberedand is saturated or unsaturated and unsubstituted or singly or multiplysubstituted; aryl, wherein aryl is unsubstituted or singly or multiplysubstituted; heteroaryl, wherein the heteroaryl is unsubstituted orsingly or multiply substituted; (C₁₋₆ alkyl)-aryl, wherein the C₁₋₆alkyl is straight-chained or branched and saturated or unsaturated andunsubstituted or singly or multiply substituted and the aryl isunsubstituted or singly or multiply substituted; or (C₁₋₆alkyl)-heteroaryl, wherein the C₁₋₆ alkyl is straight-chained orbranched and saturated or unsaturated and unsubstituted or singly ormultiply substituted and the heteroaryl is unsubstituted or singly ormultiply substituted, wherein if one of R¹ and R² is H and the other ofR¹ and R² is not H, and wherein if one of R¹ and R² represents aryl, theother of R¹ and R² represents H or C₁₋₁₂ alkyl, R³ and R⁴ independentlyof one another represent H; C₁₋₁₂ alkyl, wherein C₁₋₁₂ the alkyl isstraight-chained or branched and saturated or unsaturated andunsubstituted or singly or multiply substituted; C₃₋₈ cycloalkyl,wherein the cycloalkyl is saturated or unsaturated and unsubstituted orsingly or multiply substituted; aryl, wherein the aryl is unsubstitutedor singly or multiply substituted; heteroaryl, wherein the heteroaryl isunsubstituted or singly or multiply substituted; (C₁₋₆ alkyl)-aryl,wherein the C₁₋₆ alkyl is straight-chained or branched and saturated orunsaturated and unsubstituted or singly or multiply substituted and thearyl is unsubstituted or singly or multiply substituted; or (C₁₋₆alkyl)-heteroaryl, wherein the C₁₋₆ alkyl is straight-chained orbranched and saturated or unsaturated and unsubstituted or singly ormultiply substituted and the heteroaryl is unsubstituted or singly ormultiply substituted, wherein at least one of R³ and R⁴ is H, or one ofR¹ or R² together with one of R³ or R⁴ forms W, wherein W representsα′-(CH₂)_(n)-β′ where n=3, 4, 5, 6, 7, 8, 9 or 10; α′-CH═CH—CH₂-β′,α′-CH═CH—CH₂—CH₂-β′, α′-CH₂—CH═CH—CH₂-β′, α′-CH₂—CH₂—CH═CH—CH₂—CH₂-β′,α′-O—(CH₂)_(n)-β′ where n=2, 3, 4, 5 or 6;

where X=CH₂, O or S;

 and the end of W denoted by α′ is joined to the α-carbon atom of thecompound of formula I, and the end of W denoted by β′ is joined to theβ-carbon atom of the compound of formula I, the other of R¹ and R² is Hor C₁₋₁₂ alkyl, wherein alkyl is straight-chained or branched, saturatedor unsaturated, and unsubstituted or singly or multiply substituted, andthe other of R³ and R⁴ is H or C₁₋₁₂ alkyl, wherein alkyl isstraight-chained or branched and saturated or unsaturated andunsubstituted or singly or multiply substituted, R⁵ represents C₁₋₁₂alkyl, which is straight-chained or branched, saturated or unsaturated,and unsubstituted or singly or multiply substituted; C₃₋₈ cycloalkyl,which is saturated or unsaturated and unsubstituted or singly ormultiply substituted; heterocyclyl, wherein the heterocyclyl is 3-, 4-,5-, 6- or 7-membered and is saturated or unsaturated and unsubstitutedor singly or multiply substituted; aryl, which is unsubstituted orsingly or multiply substituted; heteroaryl, which is unsubstituted orsingly or multiply substituted; (C₁₋₆ alkyl)-aryl, wherein the C₁₋₆alkyl is straight-chained or branched and saturated or unsaturated andunsubstituted or singly or multiply substituted and the aryl isunsubstituted or singly or multiply substituted; or (C₁₋₆alkyl)-heteroaryl, wherein C₁₋₆ alkyl is straight-chained or branchedand saturated or unsaturated and unsubstituted or singly or multiplysubstituted and heteroaryl is unsubstituted or singly or multiplysubstituted, C(═O)R¹¹, CO₂H or CO₂R¹², R⁶, R⁷, R⁸ and R⁹ independentlyof one another represent H, F, Cl, Br, I, CN, NH₂, NH(C₁₋₆ alkyl),N(C₁₋₆ alkyl)₂, NH((C₁₋₆ alkyl)-aryl), N((C₁₋₆ alkyl)-aryl)₂, NH-aryl,N(aryl)₂, NHR¹³, NO₂, OH, SH; O—C₁₋₈ alkyl or S(O)_(p)—C₁₋₈ alkyl,wherein the alkyl is straight-chained or branched and saturated orunsaturated and unsubstituted or singly or multiply substituted and p is0, 1 or 2; O-aryl or S(O)_(q) aryl, wherein the aryl is unsubstituted orsingly or multiply substituted and q is 0, 1 or 2; O—(C₁₋₆ alkyl)-arylor S(O)_(r)—(C₁₋₆ alkyl)-aryl, wherein the C₁₋₆ alkyl isstraight-chained or branched and saturated or unsaturated andunsubstituted or singly or multiply substituted and the aryl isunsubstituted or singly or multiply substituted and r is 0, 1 or 2;CO₂H, C(═O)R¹⁴; C₁₋₁₂ alkyl, wherein the alkyl is straight-chained orbranched and saturated or unsaturated and unsubstituted or singly ormultiply substituted; CF₃; C₃₋₈ cycloalkyl, wherein the cycloalkyl issaturated or unsaturated and unsubstituted or singly or multiplysubstituted; heterocyclyl, which is 3-, 4-, 5-, 6- or 7-membered and issaturated or unsaturated and unsubstituted or singly or multiplysubstituted; aryl, wherein the aryl is unsubstituted or singly ormultiply substituted; or heteroaryl, wherein the heteroaryl isunsubstituted or singly or multiply substituted, or R⁶ and R⁷ togetherform Q, wherein Q represents γ′-CR¹⁵═CR¹⁶—CR¹⁷═CR¹⁸-δ′, the end of Qdenoted by γ′ is joined to the γ-carbon atom of the compound of formulaI and the end of Q denoted by δ′ is joined to the δ-carbon atom of thecompound of formula I, and Y and Z are as defined above, or R⁶ and R⁹together form T, wherein T represents γ′-CR¹⁹═CR²⁰—CR²¹═CR²²-ε′ orγ′-N═CR²⁰—CR²¹═N-ε′, the end of T denoted by γ′ is joined to theγ-carbon atom of the compound of formula I and the end of T denoted byε′ is joined to the ε-carbon atom of the compound of formula I and R⁷and R⁸ are as defined above, R¹⁰ represents C₁₋₈ alkyl, which isstraight-chained or branched and saturated or unsaturated andunsubstituted or singly or multiply substituted; C₃₋₈ cycloalkyl, whichis saturated or unsaturated and unsubstituted or singly or multiplysubstituted; heterocyclyl, which is 3-, 4-, 5-, 6- or 7-membered and issaturated or unsaturated and unsubstituted or singly or multiplysubstituted; aryl, which is unsubstituted or singly or multiplysubstituted; heteroaryl, which is unsubstituted or singly or multiplysubstituted; (C₁₋₆ alkyl)-aryl, wherein the C₁₋₆ alkyl isstraight-chained or branched and saturated or unsaturated andunsubstituted or singly or multiply substituted, and the aryl isunsubstituted or singly or multiply substituted; or (C₁₋₆alkyl)-heteroaryl, wherein the C₁₋₆ alkyl is straight-chained orbranched and saturated or unsaturated and unsubstituted or singly ormultiply substituted and the heteroaryl is unsubstituted or singly ormultiply substituted, R¹¹ represents NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆alkyl)₂, NH((C₁₋₆ alkyl)-aryl), N((C₁₋₆ alkyl)-aryl)₂, NH-aryl,N(aryl)₂, C₁₋₈ alkyl, wherein the alkyl is straight-chained or branchedand saturated or unsaturated and unsubstituted or singly or multiplysubstituted; C₃₋₈ cycloalkyl, wherein the cycloalkyl is saturated orunsaturated and unsubstituted or singly or multiply substituted; aryl,which is unsubstituted or singly or multiply substituted; heteroaryl,which is unsubstituted or singly or multiply substituted; (C₁₋₆alkyl)-aryl, wherein the C₁₋₆ alkyl is straight-chained or branched andsaturated or unsaturated and unsubstituted or singly or multiplysubstituted and the aryl is unsubstituted or singly or multiplysubstituted; or (C₁₋₆ alkyl)-heteroaryl, wherein the C₁₋₆ alkyl isstraight-chained or branched and saturated or unsaturated andunsubstituted or singly or multiply substituted and the heteroaryl isunsubstituted or singly or multiply substituted, R¹² represents C₁₋₈alkyl, wherein the alkyl is straight-chained or branched and saturatedor unsaturated and unsubstituted or singly or multiply substituted; C₃₋₈cycloalkyl, wherein the cycloalkyl is saturated or unsaturated andunsubstituted or singly or multiply substituted; (C₁₋₆ alkyl)-aryl,wherein the C₁₋₆ alkyl is straight-chained or branched and saturated orunsaturated and unsubstituted or singly or multiply substituted and thearyl is unsubstituted or singly or multiply substituted, R¹³ representsC(═O)CH₃, C(═O) phenyl or C(═O)O-t.-butyl(t-BOC), R¹⁴ represents H, NH₂,NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, NH((C₁₋₆ alkyl)-aryl), N((C₁₋₆alkyl)-aryl)₂, NH-aryl, N(aryl)₂, C₁₋₈ alkyl, wherein the alkyl isstraight-chained or branched and saturated or unsaturated andunsubstituted or singly or multiply substituted; C₃₋₈ cycloalkyl, whichis saturated or unsaturated and unsubstituted or singly or multiplysubstituted; aryl, which is unsubstituted or singly or multiplysubstituted; (C₁₋₆ alkyl)-aryl, wherein the C₁₋₆ alkyl isstraight-chained or branched and saturated or unsaturated andunsubstituted or singly or multiply substituted, and the aryl isunsubstituted or singly or multiply substituted; OC₁₋₈ alkyl, whereinthe alkyl is straight-chained or branched and saturated or unsaturatedand unsubstituted or singly or multiply substituted; OC₃₋₈ cycloalkylwherein the cycloalkyl is saturated or unsaturated and unsubstituted orsingly or multiply substituted; O-aryl, wherein the aryl isunsubstituted or singly or multiply substituted, or O—(C₁₋₆ alkyl)-aryl,wherein the C₁₋₆ alkyl is straight-chained or branched and saturated orunsaturated and unsubstituted or singly or multiply substituted, and thearyl is unsubstituted or singly or multiply substituted, R¹⁵, R¹⁶, R¹⁷and R¹⁸ independently of one another represent H, F, Cl, Br, I, OH, CN;C₁₋₈ alkyl, wherein alkyl is straight-chained or branched and saturatedor unsaturated and unsubstituted or singly or multiply substituted; orCO₂H, and R¹⁹, R²⁰, R²¹ and R²² independently of one another representH, F, Cl, Br, I, CN, OH; C₁₋₈ alkyl, wherein alkyl is straight-chainedor branched and saturated or unsaturated and unsubstituted or singly ormultiply substituted; or CO₂H, and a pharmaceutically acceptable saltthereof
 2. A compound according to claim 1, in the form of a racemate ora pure enantiomer.
 3. A compound according to claim 1, in the form of amixture of enantiomers, or in the form of a mixture of diastereomers inany mixing ratio.
 4. A compound according to claim 1, wherein Yrepresents N, Z represents CR⁹, one of R¹ and R² represents OR¹⁰, SR¹⁰,C₁₋₆ alkyl or aryl, one of R³ and R⁴ represents H or C₁₋₆ alkyl, or oneof R¹ and R² together with one of R³ and R⁴ forms W, wherein Wrepresents α′-CH═CH—CH₂—CH₂-β′,

 and the two other radicals from R¹, R², R³ and R⁴ represent H or C₁₋₁₂alkyl, R⁵ represents C₃₋₇ cycloalkyl, heteroaryl, C(═O)R¹¹, CO₂H orCO₂R¹², R⁶ represents H, F, Cl, Br, CN, NO₂, C(═O)R¹⁴, C₁₋₆ alkyl, CF₃or aryl, R⁷ represents H, F, Cl, Br, CN, NH₂, OH or C₁₋₆ alkyl, R⁹represents H, OH, CF₃ or C₁₋₆ alkyl or R⁶ and R⁹ together form T,wherein T represents γ′-N═CR²⁰—CR²¹═N-ε′, R¹⁰ represents C₁₋₈ alkyl oraryl, R¹¹ represents aryl, R¹² represents C₁₋₆ alkyl, R¹⁴ representsOC₁₋₆ alkyl, R²⁰ represents H or CH₂H and R²¹ represents H.
 5. Acompound according to claim 3, wherein one of R¹ and R² representsO—(CH₂)₂—OH, S-phenyl, phenyl, 3-methylphenyl, 2,4-dimethylphenyl,4-hydroxyphenyl, 4-methoxyphenyl, 4-hydroxy-3-methoxyphenyl,3,4-dimethoxyphenyl or 2-naphthyl, one of R³ and R⁴ represents H ormethyl, or one of R¹ and R² together with one of R³ and R⁴ forms W,wherein W represents α′-CH═CH—CH₂—CH₂-β′,

 or

and the other two of R¹, R², R³ and R⁴ represent H, R⁵ representscyclopropyl, 2-(C(═O)O-ethyl)-cyclopropyl, cyclohexyl, 2-pyridinyl,C(═O) phenyl, CO₂H or CO₂ ethyl, R⁶ represents H, Br, CO₂ ethyl ormethyl, R⁷ represents H, NH₂, OH or methyl and R⁹ represents H, Cl, OHor CF₃ or R⁶ and R⁹ together form T, wherein T representsγ′-N═C(CO₂H)—CH═N-ε′.
 6. A compound according to claim 4, selected fromthe group consisting of:7-bromo-4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrimido[1,2a]pyrimidine-2-carboxylicacid ethyl ester,7-bromo-4-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H-pyrimido[1,2-a]pyrimidine-2-carboxylicacid,7-bromo-4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrimido[1,2a]pyrimidine-2-carboxylicacid,7-bromo-4-(4-hydroxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrimido[1,2-a]pyrimidine-2-carboxylicacid ethyl ester,2-bromo-6,6a,7,11b-tetrahydro-4,5,11c-triaza-benzo[c]fluorene-6-carboxylicacid ethyl ester,7-bromo-4-(4-methoxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrimido[1,2a]pyrimidine-2-carboxylicacid,7-bromo-4-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H-pyrimido[1,2-a]pyrimidine-2-carboxylicacid,7-bromo-4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrimido[1,2a]pyrimidine-2-carboxylicacid,[7-bromo-4-(2-hydroxy-ethoxy)-3,4-dihydro-2H-pyrimido[1,2a]pyrimidin-2-yl]-phenyl-methanone,[7-bromo-4-(4-hydroxy-3-methoxy-phenyl)-3-methyl-3,4-dihydro-2Hpyrimido[1,2a]pyrimidin-2-yl]-phenyl-methanone,[7-bromo-4-(4-methoxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrimido[1,2-a]pyrimidin-2-yl]-phenyl-methanone,[7-bromo-4-(4-hydroxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrimido[1,2-a]pyrimidin-2-yl]-phenyl-methanone,[7-bromo-4-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H-pyrimido[1,2-a]pyrimidin-2-yl]-phenyl-methanone,[7-bromo-4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrimido[1,2a]pyrimidin-2-yl]-phenyl-methanone,2-(7-bromo-2-cyclopropyl-3,4-dihydro-2H-pyrimido[1,2a]pyrimidin-4-yloxy)-ethanol,2-(7-bromo-2-cyclohexyl-3,4-dihydro-2H-pyrimido[1,2a]pyrimidin-4-yloxy)-ethanol,4-(7-bromo-2-cyclohexyl-3-methyl-3,4-dihydro-2H-pyrimido[1,2-a]pyrimidin-4-yl)-phenol,7-bromo-4-naphthalen-2-yl-3,4-dihydro-2H-pyrimido[1,2a]pyrimidine-2-carboxylicacid ethyl ester,7-bromo-4-m-tolyl-3,4-dihydro-2H-pyrimido[1,2a]pyrimidine-2 carboxylicacid ethyl ester,2-[7-bromo-4-(2,4-dimethyl-phenyl)-3,4-dihydro-2H-pyrimido[1,2-a]pyrimidin-2-yl]-cyclopropanecarboxylic acid ethyl ester,2-[7-bromo-4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrimido[1,2-a]pyrimidin-2-yl]-cyclopropanecarboxylic acid ethyl ester,7-bromo-4-phenylsulphanyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrimido[1,2-a]pyrimidine,2-chloro-6-phenylsulphanyl-8-pyridin-2-yl-7,8-dihydro-6H-pyrimido[1,2-a]pyrimidin-4-yl-amine,6-phenylsulphanyl-8-pyridin-2-yl-7,8-dihydro-6H-pyrimido[1,220a]pyrimidine-2,4-diol,6-phenylsulphanyl-8-pyridin-2-yl-2-trifluoromethyl-7,8-dihydro-6H-pyrimido[1,2a]pyrimidine-3-carboxylicacid ethyl ester,3-methyl-5,8-methano-9-pyridin-2-yl-5,8,8a,9-tetrahydro-4bH-1,4a,10-triaza-phenanthrene-2,4-diol,5,8-methano-9-pyridin-2-yl-5,8,8a,9-tetrahydro-4bH-1,4a,10-triaza-phenanthrene-2,4-diol,12-hydroxyl-1,4-methano-5-pyridin-2-yl-1,4a,5,12b-tetrahydro-4H-6,7,8,11,12a-pentaaza-benzo[a]anthracene-10-carboxylicacid, and3-bromo-9-pyridin-2-yl-7,8,8a,9-tetrahydro-4bH-1,4a,10-triaza-phenanthrene.7. A compound according to claim 2, wherein Y represents CR⁸, Zrepresents N, one of R¹ and R² represents OR¹⁰, SR¹⁰, C₁₋₆ alkyl oraryl, R³ and R⁴ represents H or C₁₋₆ alkyl, or one of R¹ and R² togetherwith one of R³ and R⁴ forms W, wherein W represents

and the other two of R¹, R², R³ and R⁴ represent H or C₁₋₁₂ alkyl, R⁵represents C₃₋₇ cycloalkyl, heteroaryl, C(═O)R¹¹, CO₂H or CO₂R¹², R⁶represents H, F, Cl, Br, CN, NO₂, C(═O)R¹⁴, C₁₋₆ alkyl, CF₃ or aryl, R⁷represents H, F, Cl, Br, CN, NH₂, OH or C₁₋₆ alkyl, R⁸ represents H, F,Cl, Br, CN, NO₂, O—(C₁₋₆ alkyl)-aryl, CO₂H, CONH₂ or C₁₋₆ alkyl, R¹⁰represents C₁₋₈ alkyl or aryl, R¹¹ represents aryl, R¹² represents C₁₋₆alkyl and R¹⁴ represents OC₁₋₆ alkyl.
 8. A compound according to claim7, wherein one of R¹ and R² represents O—(CH₂)₂—OH, S-phenyl, phenyl,3-methylphenyl, 2,4-dimethylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl,4-hydroxy-3-methoxyphenyl or 3,4-dimethoxyphenyl, one of R³ and R⁴represents H or methyl, or one of R¹ and R² together with one of R³ andR⁴ forms W, wherein W represents

and the other two of R¹, R², R³ and R⁴ represent H, R⁵ representscyclopropyl, 2-(C(═O)O-ethyl)-cyclopropyl, cyclohexyl, 2-pyridinyl,5-methyl-furan-2-yl, 5-nitro-furan-2-yl, C(═O) phenyl, CO₂H or CO₂ethyl, R⁶ represents H, Cl, CN or phenyl, R⁷ represents H, NH₂ or CN andR⁸ represents H, Cl, CN, CO₂H or CONH₂.
 9. A compound according to claim7, selected from the group consisting of:4-(4-methoxy-phenyl)-3-methyl-2-(5-nitro-furan-2-yl)-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine,2-[4-(4-methoxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrazino[1,2a]pyrimidin-2-yl]-cyclopropanecarboxylic acid ethyl ester,4-(4-methoxy-phenyl)-3-methyl-2-(5-methyl-furan-2-yl)-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine,4-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine-2-carboxylicacid ethyl ester,4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine-2-carboxylicacid ethyl ester,4-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine-2-carboxylicacid,4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine-2-carboxylicacid,4-(4-methoxy-phenyl)-2-(5-nitro-furan-2-yl)-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine,2-[4-(2,4-dimethyl-phenyl)-3,4-dihydro-2H-pyrazino[1,2a]pyrimidin-2-yl]-cyclopropanecarboxylic acid ethyl ester,2-[4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrazino[1,2a]pyrimidin-2-yl]-cyclopropanecarboxylic acid ethyl ester,4-(4-hydroxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine-2-carboxylicacid ethyl ester, 6,6a,7,11 b-tetrahydro-3,5,11c-triaza-benzo[c]fluorene-6-carboxylic acid ethyl ester,4-phenylsulphanyl-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine-2-carboxylicacid ethyl ester,4-phenylsulphanyl-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine-2-carboxylicacid,4-(4-methoxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine-2-carboxylicacid,4-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine-2-carboxylicacid,4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine-2-carboxylicacid,[4-(2-hydroxy-ethoxy)-3,4-dihydro-2H-pyrazino[1,2a]pyrimidin-2-yl]-phenyl-methanone,[4-(4-hydroxy-3-methoxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrazino[1,2a]pyrimidin-2-yl]-phenyl-methanone,[4-(4-methoxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrazino[1,2a]pyrimidin-2-yl]-phenyl-methanone,[4-(4-hydroxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrazino[1,2a]pyrimidin-2-yl]-phenyl-methanone,2-cyclopropyl-4-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine,2-cyclopropyl-4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrazino[1,2-a]pyrimidine,2-(2-cyclohexyl-3,4-dihydro-2H-pyrazino[1,2a]pyrimidin-4-yloxy)ethanol,2-cyclohexyl-4-(4-methoxy-phenyl)-3,4-dihydro-2H-pyrazino[1,2-a]pyrimidine,4-methyl-2-(5-nitro-furan-2-yl)-4-phenyl-3,4-dihydro-2H-pyrazino[1,2-a]pyrimidine,2-(4-methyl-4-phenyl-3,4-dihydro-2H-pyrazino[1,2a]pyrimidin-2-yl)-cyclopropanecarboxylic acid ethyl ester,4-phenyl-2-pyridin-2-yi-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine,4-phenyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine-9-carboxylicacid,6-amino-7-chloro-4-phenyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrazino[1,2-a]pyrimidine-9-carboxylicacid amide,2-phenylsulphanyl-3-pyridin-2-yl-2,3-dihydro-1H-pyrimido[1,2a]quinolin-10-ol,4-phenylsulphanyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrazino[1,2-a]pyrimidine-9-carboxylicacid,6-amino-7-chloro-4-phenylsulphanyl-2-pyridin-2-yl-3,4-dihydro-2H-pyrazino[1,2a]pyrimidine-9-carboxylicacid amide,7-phenyl-4-phenylsulphanyl-2-pyridin-2-yl-3,4-.dihydro-2H-pyrazino[1,2a]pyrimidine-9-carbonitrile,5,8-methano-9-pyridin-2-yl-5,8,8a,9-tetrahydro-4bH-2,4a,10-triaza-phenanthrene,and1-chloro-5,8-methano-9-pyridin-2-yl-5,8,8a,9-tetrahydro-4bH-2,4a,10-triaza-phenanthrene-3,4-dicarbonitrile.10. A method for producing a compound of according to claim 1,comprising reacting a heteroarylamine of formula II

wherein Y, Z, R⁶ and R⁷ are as defined for formula I, with the provisothat if R⁶ and R⁷ form Q as defined for formula I, the end of Q denotedby γ′ is joined to the γ-carbon atom of the heteroarylamine of formulaII and the end of Q denoted by δ′ is joined to the δ-carbon atom of theheteroarylamine of formula II, and that if R⁶ and R⁹ form T as definedfor formula I, the end denoted by γ′ is joined to the γ-carbon atom ofthe heteroarylamine of formula II and the end denoted by ε′ is joined tothe ε-carbon atom of the heteroarylamine of formula II, with an aldehydeof formula III

wherein R⁵ is as defined for formula I, and an olefin of formula IV

wherein R¹, R², R³ and R⁴ are as defined for formula I, with the provisothat if one of R¹ and R² together with one of R³ and R⁴ forms W, the endof W denoted by α′ is joined to the α-carbon atom of the olefin offormula IV and the end of W denoted by β′ is joined to the β-carbon atomof the olefin of formula IV, in the presence of an acid.
 11. A methodaccording to claim 9, wherein the heteroarylamine of formula II isreacted with the aldehyde of formula III and the olefin of formula IV bya one pot method.
 12. A method according to claim 10, wherein the acidis trifluoroacetic acid.
 13. A method according to claim 11, wherein thereaction is carried out in an organic solvent at a temperature of 0 to100° C. with a reaction time of 0.25 to 12 h.
 14. A method according toclaim 12, wherein the reaction is carried out at a temperature of 15 to40° C.
 15. A method according to claim 13, wherein the organic solventis acetonitrile.
 16. A substance library comprising at least onecompound of claim
 1. 17. A pharmaceutical composition comprising atleast one compound of claim 1 and a pharmaceutically acceptableexcipient.
 18. A method for treating pain in a mammal, comprisingadministering to a mammal in need thereof an effective amount of thepharmaceutical composition of claim
 17. 19. A method according to claim18, wherein the mammal is human.
 20. A method for treating at least onecondition selected from the group consisting of urinary incontinence,itching, tinnitus, aurium and diarrhea in a mammal, comprisingadministering to a mammal in need thereof a therapeutically effectiveamount of a pharmaceutical composition of claim
 17. 21. A methodaccording to claim 20, wherein the mammal is human.